Activation of STAT3 (signal transducer and activator of transcription 3) plays a crucial role in cell survival and proliferation. The aim of the present study was to clarify the role of STAT3 signalling in the protection of polyamine-depleted intestinal epithelial cells against TNF-α (tumour necrosis factor-α)-induced apoptosis. Polyamine depletion by DFMO (α-difluoromethylornithine) caused phosphorylation of STAT3 at Tyr-705 and Ser-727. Phospho-Tyr-705 STAT3 was immunolocalized at the cell periphery and nucleus, whereas phospho-Ser-727 STAT3 was predominantly detected in the nucleus of polyamine-depleted cells. Sustained phosphorylation of STAT3 at tyrosine residues was observed in polyamine-depleted cells after exposure to TNF-α. Inhibition of STAT3 activation by AG490 or cell-membrane-permeant inhibitory peptide (PpYLKTK; where pY represents phospho-Tyr) increased the sensitivity of polyamine-depleted cells to apoptosis. Expression of DN-STAT3 (dominant negative-STAT3) completely eliminated the protective effect of DFMO against TNF-α-induced apoptosis. Polyamine depletion increased mRNA and protein levels for Bcl-2, Mcl-1 (myeloid cell leukaemia-1) and c-IAP2 (inhibitor of apoptosis protein-2). Significantly higher levels of Bcl-2 and c-IAP2 proteins were observed in polyamine-depleted cells before and after 9 h of TNF-α treatment. Inhibition of STAT3 by AG490 and DN-STAT3 decreased Bcl-2 promoter activity. DN-STAT3 decreased mRNA and protein levels for Bcl-2, Mcl-1 and c-IAP2 in polyamine-depleted cells. siRNA (small interfering RNA)-mediated inhibition of Bcl-2, Mcl-1 and c-IAP2 protein levels increased TNF-α-induced apoptosis. DN-STAT3 induced the activation of caspase-3 and PARP [poly(ADP-ribose) polymerase] cleavage in polyamine-depleted cells. These results suggest that activation of STAT3 in response to polyamine depletion increases the transcription and subsequent expression of anti-apoptotic Bcl-2 and IAP family proteins and thereby promotes survival of cells against TNF-α-induced apoptosis.
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Research Article|
November 22 2005
STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells
Sujoy Bhattacharya;
Sujoy Bhattacharya
1Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, U.S.A.
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Ramesh M. Ray;
Ramesh M. Ray
1
1Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, U.S.A.
1To whom correspondence should be addressed (email rray@physio1.utmem.edu).
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Leonard R. Johnson
Leonard R. Johnson
1Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, U.S.A.
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Publisher: Portland Press Ltd
Received:
March 18 2005
Revision Received:
June 29 2005
Accepted:
July 28 2005
Accepted Manuscript online:
July 28 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 392 (2): 335–344.
Article history
Received:
March 18 2005
Revision Received:
June 29 2005
Accepted:
July 28 2005
Accepted Manuscript online:
July 28 2005
Citation
Sujoy Bhattacharya, Ramesh M. Ray, Leonard R. Johnson; STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. Biochem J 1 December 2005; 392 (2): 335–344. doi: https://doi.org/10.1042/BJ20050465
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